Vitamin D deficiency is highly prevalent in patients with advanced chronic kidney disease (CKD). Cardiovascular disease (CVD) and infection are the top causes of morbidity and mortality in CKD and end- stage renal disease (ESRD). Evidence generated by the candidate's (Ravi Thadhani, MD, MPH) laboratory has linked CVD progression and altered immune response to inadequate vitamin D levels in CKD/ESRD. Under Dr. Thadhani's direction, a comprehensive patient-oriented research program seeks to investigate the relationship between vitamin D biology and supplementation strategies in terms of mechanistic and clinically relevant endpoints. This application describes three unique aims in three studies (each backed by separate funding sources) that will be pursued by the candidate and his trainees: (1) in DIVINE - an NIH sponsored trial of nutritional vitamin D - his team will determine whether nutritional vitamin D deficiency in ESRD patients leads to altered macrophage function and ex-vivo response to infection; (2) in PRIMO - an industry sponsored trial of active vitamin D and left ventricular hypertrophy [LVH], diastolic function, and cardiac hospitalization in patients with stage 3/4 CKD - his team will determine if baseline levels of 25-hydroxy vitamin D (25D) and fibroblast growth factor-23 (FGF-23) are linked to progression or lack of regression of LVH; and (3) in LUCID - a prospective cohort of incident ESRD subjects supported by the Canadian Institutes of Health - his team will examine whether active vitamin D leads to excess coronary artery calcification. By supporting the candidate's request for this K24 award, important patient-oriented questions will be addressed. Moreover, Dr. Thadhani, with an exemplary record of mentorship, teaching and research, will be afforded the necessary protected time to mentor individuals who comprise a new generation of clinical research fellows and students in Nephrology.